Tracking clonal structure from leukemia diagnosis to relapse using mitochondrial variants
department or school: Science, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Tam, Derek
issued: 2025-10-31T07:00:00Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults, characterized by clonal expansion of immature blood cells that leads to bone marrow failure. AML is a heterogeneous disease despite its low mutational burden, leading to a relapse rate of over 60\% within five years of diagnosis. Relapse is attributed to the persistence of leukemic stem cells which emerge from clonal molecular heterogeneity, eventually repopulating the marrow. Understanding how clonal structure evolves is essential for comprehending the factors involved in relapse. Recently, a novel method for assaying clonal structure using mitochondrial variants was reported. Mitochondrial DNA is reported to have a 10- to 100-fold increased mutation rate relative to nuclear DNA, and these mutations are inherited in a stochastic manner with each cell division. These properties make mitochondrial variants particularly useful as endogenous barcodes from which clonal relationships can be reconstructed. In this thesis, I first reproduce this method in a synthetic experiment to validate the findings and assess the sensitivity of the assay. I then develop a single-cell DNA-sequencing panel that can infer clonal structure using a combination of nuclear and mitochondrial variants. I apply this method to longitudinal bone marrow samples collected from AML patients before treatment and after relapse. Assessment of changes to clone frequency between timepoints revealed that 40\% of cases were clonally stable based on mutations in nuclear DNA. However, reassessment of the clonal structure using mitochondrial DNA reveals that half of these stable cases exhibit a subclonal change in structure that is not linked to a mutational change. This work suggests that non-genetic factors play a role in modifying clone fitness and should be examined in combination with genetic changes to fully understand how clones respond to and evade treatment, ultimately resulting in a high rate of relapse.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/89581
note: TRACKING CLONAL STRUCTURE FROM LEUKEMIA DIAGNOSIS TO RELAPSEUSING MITOCHONDRIAL VARIANTSbyDEREK TAMB.Sc. (Hons), The University of British Columbia, 2018A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES(Bioinformatics)THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)October 2024© Derek Tam, 2024The following individuals certify that they have read, and recommend to the Faculty of Graduate andPostdoctoral Studies for acceptance, the thesis entitled:Tracking clonal structure from leukemia diagnosis to relapse using mitochondrial variantssubmitted by Derek Tam in partial fulfillment of the requirements forthe degree of Master of Sciencein BioinformaticsExamining Committee:Dr. Aly Karsan, Professor, Pathology & Laboratory Medicine, UBCCo-supervisorDr. Andrew Roth, Assistant Professor, Pathology & Laboratory Medicine, and Computer Science, UBCCo-supervisorDr. Yongjin Park, Assistant Professor, Pathology & Laboratory Medicine, and Statistics, UBCSupervisory Committee MemberDr. Adi Steif, Assistant Professor, Medical Genetics, UBCAdditional ExaminerDr. Alexander Wyatt, Associate Professor, Urologic Sciences, UBCAdditional ExaminerAdditional Supervisory Committee Members:Dr. Geoffrey Schiebinger, Assistant Professor, Mathematics, UBCSupervisory Committee MemberiiAbstractAcute myeloid leukemia (AML) is the most common form of acute leukemia in adults,characterized by clonal expansion of immature blood cells that leads to bone marrow failure.AML is a heterogeneous disease despite its low mutational burden, leading to a relapse rate ofover 60% within five years of diagnosis. Relapse is attributed to the persistence of leukemic stemcells which emerge from clonal molecular heterogeneity, eventually repopulating the marrow.Understanding how clonal structure evolves is essential for comprehending the factors involvedin relapse. Recently, a novel method for assaying clonal structure using mi…
has type: Thesis/Dissertation
date issued: 2025-05
is shown at: 10.14288/1.0447180
language: eng
degree discipline: Bioinformatics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Karsan, Aly
contributor: Roth, Andrew J. L.
type: Text
identifier URI: http://hdl.handle.net/2429/89581